**4. Discussion**

The findings of the current meta-analyses are consistent with the clinical experiences and recommendations of traditional Ayurvedic literature. The two promising herbs for clinical improvements in hypercholesterolemia were found to be garlic and guggulu. This systematic review and meta-analysis suggested that Ayurvedic herbal preparations are safe and effective in reducing major cholesterol biomarkers. In addition to the studies conducted on these four interventions, 32 randomized controlled studies found out that there are 10 additional Ayurvedic interventions such as holy basil, ginger, fenugreek, and Indian gooseberry, which are capable of correcting hypercholesterolemia. However, a majority of studies were conducted on garlic, guggulu, *Nigella sativa,* and *Lashunadi guggulu* (a garlic and guggulu combination). It was also observed that amongs<sup>t</sup> all of these Ayurvedic interventions, garlic and guggulu stood out as the most effective interventions. Although *Lashunadi guggulu* topped the list in its effectiveness, due to the lack of enough number of studies, the strength of the evidence on this finding is fairly low. Garlic and guggulu had the most consistent effects on cholesterol, except garlic did not seem to be as effective in increasing HDL-C as compared to guggulu. Both garlic and guggulu were not found to be effective in reducing TG levels, as the effect size was not statistically significant. Studies on garlic were less heterogeneous than studies conducted on guggulu. However, the overall effect size of guggulu exceeds that of garlic.

#### *4.1. Commiphora Mukul (Guggulu)*

Amongst all of the Ayurvedic interventions studied, *Commiphora mukul*, commonly known as guggul(u) was found to have the biggest effect size. Seven randomized controlled trials in eight trial arms enrolling a total of 380 participants compared guggulu with a placebo for its effect on various cholesterol levels. It was observed that guggulu reduces TC by 16.78 mg/dL (95% C.I.: 30.96 to 2.61, *p* value = 0.02) and LDL-C by 18.78 mg/dL (95% C.I.: 34.07 to 3.48, *p* value = 0.02). These findings on guggulu came from the analysis of end results from eight trial arms of seven RCTs involving 380 people (184 in the control group and 197 in the experimental group). One of the studies included in this analysis [66] seems to have had a big influence on the overall effect of this intervention. Heterogeneity among these seven studies was 75%, which still allowed the conduction of the metaanalysis. Likewise, as compared to a placebo, guggulu reduced TG levels by 7.35 mg/dL (95% C.I.: 23.29 to 8.59; *p* value = 0.37) and raised HDL-C by 2.19 mg/dL (95% C.I. 0.27 to 4.12; *p*-value = 0.03). This effect size counts for a reduction in TC and LDL-C by nearly 6.5% and 10%, respectively. This finding is of clinical significance, as it is associated with a 38% reduction in the risk of coronary events at age 50 (Law et. al, 1994) [69]. The risk of coronary events is *dependent* on other cardiovascular risk factors such as hypertension and age. In addition, it is also understood that a 10% reduction in LDL-C levels helps minimize the risk of coronary and vascular events [70]. Out of eight trial arms included in analysis, all but two studies [21,47] were conducted in the Western population with a typical Western diet. When a sensitivity analysis was performed by excluding these two studies, then the effect size was 22.85 (95% C.I.: 40.74, 4.97). Another possibility is that the discrepancies are due to the dietary habits of Indian and Western populations. Another postulation could be that this native Indian plant is better suited to natives of India—as the Vedic scriptures say, "local plants and herbs are best suited to the local people" [71].

One of the studies included in the analysis of guggulu is Verma (1988) [66] and shows a bigger effect size. However, this study included patients with a baseline total cholesterol level of 275 mg/dL or more or triglycerides levels of 200 mg/dL. Thus, there is a possibility that guggulu is more effective when the baseline cholesterol and triglyceride levels are high. Moreover, Verma (1988) describes the process of purification of guggulu. Purification of guggulu is also associated with its chances of posing any side effects. Although there were no serious adverse events posed by guggulu, a small proportion of participants did experience diarrhea, headaches, and skin rashes. These side effects are minimal when compared to the threats posed by conventional drug therapy. Purified guggulu seems to have fewer side effects. The study by Szapary et al. [21], which showed negative effects of guggulu, did not mention if the product was purified as per the Ayurvedic protocol or not. Additionally, the study included an extracted version of guggulu prepared by a commercial manufacturer. Thus, there is an inherent chance of bias despite the fact that it was the first methodologically sound randomized controlled trial conducted on guggulu in the West. When asked for further comments, no response was received from the principal author [21].

So far, the types of guggulu used for clinical trials are very diverse. Some studies used purified crude gum guggulu as recommended by Ayurvedic texts, whereas others used a guggulu extract called guggulipid. Guggulipid is extracted from the plant by using ethyl acetate and is mixed with petroleum ether to produce a product called fraction A [26]. This fraction A guggulu has been used in some trials. Extracting the active ingredient of guggulu is not an Ayurvedic practice, so it might be a plausible reason for this observation. Guggulu has been qualitatively reviewed by few several groups of researchers in the past [16,26,72]. So far, none of the reviews conducted a meta-analysis of guggulu studies. This work is first of its kind and thus cannot be compared with any previous meta-analysis. In summary, guggulu is moderately effective in terms of total cholesterol, LDL-C, and HDL-C, and there is a strong evidence to this end. Thus, it can be recommended as an adjuvant to cholesterol-lowering pharmacological therapy or as a supplement to a healthier diet and lifestyle for those who have borderline cholesterol levels.
